tbuckley/cabot-search huggingface dataset:
Metal-enriched HSP90 nanoinhibitor overcomes heat resistance in hyperthermic intraperitoneal chemotherapy used for peritoneal metastases
Authors: Qiang Wang, Peng Liu, Yingfei Wen, Kuan Li, Bo Bi, Bin-bin Li, Miaojuan Qiu, Shiqiang Zhang, You Li, Jia Li, Hengxing Chen, Yuan Yin, Leli Zeng, Changhua Zhang, Yulong He, Jing Zhao
Journal: Molecular Cancer (2023)

Abstract Clinical hyperthermic intraperitoneal chemotherapy (HIPEC) is regarded as a potential treatment that can prolong survival of patients with peritoneal metastases after cytoreductive surgery. However, treated tumor cells are prone to becoming heat resistant to HIPEC therapy through high expression of heat shock proteins (HSPs). Here, a carrier-free bifunctional nanoinhibitor was developed for HIPEC therapy in the management of peritoneal metastases. Self-assembly of the nanoinhibitor was formed by mixing Mn ion and epigallocatechin gallate (EGCG) in a controllable manner. Such nanoinhibitor directly inhibited HSP90 and impaired the HSP90 chaperone cycle by reduced intracellular ATP level. Additionally, heat and Mn ion synergistically induced oxidative stress and expression of caspase 1, which activated GSDMD by proteolysis and caused pyroptosis in tumor cells, triggering immunogenic inflammatory cell death and induced maturation of dendritic cells through the release of tumor antigens. This strategy to inhibit heat resistance in HIPEC presented an unprecedented paradigm for converting “cold” tumors into “hot” ones, thus significantly eradicating disseminated tumors located deep in the abdominal cavity and stimulating immune response in peritoneal metastases of a mouse model. Collectively, the nanoinhibitor effectively induced pyroptosis of colon tumor cells under heat conditions by inhibiting heat stress resistance and increasing oxidative stress, which may provide a new strategy for treatment of colorectal peritoneal metastases.
Applications of long-read sequencing to Mendelian genetics
Authors: Francesco Kumara Mastrorosa, Danny E. Miller, Evan E. Eichler
Journal: Genome Medicine (2023)

Advances in clinical genetic testing, including the introduction of exome sequencing, have uncovered the molecular etiology for many rare and previously unsolved genetic disorders, yet more than half of individuals with a suspected genetic disorder remain unsolved after complete clinical evaluation. A precise genetic diagnosis may guide clinical treatment plans, allow families to make informed care decisions, and permit individuals to participate in N-of-1 trials; thus, there is high interest in developing new tools and techniques to increase the solve rate. Long-read sequencing (LRS) is a promising technology for both increasing the solve rate and decreasing the amount of time required to make a precise genetic diagnosis. Here, we summarize current LRS technologies, give examples of how they have been used to evaluate complex genetic variation and identify missing variants, and discuss future clinical applications of LRS. As costs continue to decrease, LRS will find additional utility in the clinical space fundamentally changing how pathological variants are discovered and eventually acting as a single-data source that can be interrogated multiple times for clinical service.
Tau pathology in neurodegenerative disease: disease mechanisms and therapeutic avenues
Authors: Niyatee Samudra, Courtney Lane-Donovan, Lawren VandeVrede, Adam L. Boxer
Journal: Journal of Clinical Investigation (2023)

Tauopathies are disorders associated with tau protein dysfunction and insoluble tau accumulation in the brain at autopsy. Multiple lines of evidence from human disease, as well as nonclinical translational models, suggest that tau has a central pathologic role in these disorders, historically thought to be primarily related to tau gain of toxic function. However, a number of tau-targeting therapies with various mechanisms of action have shown little promise in clinical trials in different tauopathies. We review what is known about tau biology, genetics, and therapeutic mechanisms that have been tested in clinical trials to date. We discuss possible reasons for failures of these therapies, such as use of imperfect nonclinical models that do not predict human effects for drug development; heterogeneity of human tau pathologies which may lead to variable responses to therapy; and ineffective therapeutic mechanisms, such as targeting of the wrong tau species or protein epitope. Innovative approaches to human clinical trials can help address some of the difficulties that have plagued our field's development of tau-targeting therapies thus far. Despite limited clinical success to date, as we continue to refine our understanding of tau's pathogenic mechanism(s) in different neurodegenerative diseases, we remain optimistic that tau-targeting therapies will eventually play a central role in the treatment of tauopathies.
Autonomous IL-36R signaling in neutrophils activates potent antitumor effector functions
Authors: Sumedha Roy, Karen Fitzgerald, Almin Lalani, Chin-Wen Lai, Aeryon Kim, Jennie Kim, Peiqi Ou, Annie Mirsoian, Xian Liu, Ambika Ramrakhiani, Huiren Zhao, Hong Zhou, Haoda Xu, Hans Meisen, Chi-Ming Li, Bryan Vander Lugt, Steve Thibault, Christine E. Tinberg, Jason DeVoss, Jackson Egen, Lawren C. Wu, Rajkumar Noubade
Journal: Journal of Clinical Investigation (2023)

While the rapid advancement of immunotherapies has revolutionized cancer treatment, only a small fraction of patients derive clinical benefit. Eradication of large, established tumors appears to depend on engaging and activating both innate and adaptive immune system components to mount a rigorous and comprehensive immune response. Identifying such agents is a high unmet medical need, because they are sparse in the therapeutic landscape of cancer treatment. Here, we report that IL-36 cytokine can engage both innate and adaptive immunity to remodel an immune-suppressive tumor microenvironment (TME) and mediate potent antitumor immune responses via signaling in host hematopoietic cells. Mechanistically, IL-36 signaling modulates neutrophils in a cell-intrinsic manner to greatly enhance not only their ability to directly kill tumor cells but also promote T and NK cell responses. Thus, while poor prognostic outcomes are typically associated with neutrophil enrichment in the TME, our results highlight the pleiotropic effects of IL-36 and its therapeutic potential to modify tumor-infiltrating neutrophils into potent effector cells and engage both the innate and adaptive immune system to achieve durable antitumor responses in solid tumors.
2,5-dimethylcelecoxib alleviated NK and T-cell exhaustion in hepatocellular carcinoma via the gastrointestinal microbiota-AMPK-mTOR axis
Authors: Banglun Pan, Zhanfei Chen, Xiaoxia Zhang, Zengbin Wang, Yuxin Yao, Xiaoxuan Wu, Jiacheng Qiu, Hua Lin, Liumin Yu, Haijian Tu, Nanhong Tang
Journal: Journal for ImmunoTherapy of Cancer (2023)

2,5-dimethylcelecoxib (DMC), a derivative of celecoxib, is an inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1). Our previous studies have demonstrated that DMC inhibits the expression of programmed death-ligand 1 on hepatocellular carcinoma (HCC) cells to prevent tumor progression. However, the effect and mechanism of DMC on HCC infiltrating immune cells remain unclear. In this study, single-cell-based high-dimensional mass cytometry was performed on the tumor microenvironment of HCC mice treated with DMC, celecoxib and MK-886 (a known mPGES-1 inhibitor). Moreover, 16S ribosomal RNA sequencing was employed to analyze how DMC improved the tumor microenvironment of HCC by remodeling the gastrointestinal microflora. We found that (1) DMC significantly inhibited the growth of HCC and improved the prognosis of the mice, and this depended on the stronger antitumor activity of natural killer (NK) and T cells; (2) compared with celecoxib and MK-886, DMC significantly enhanced the cytotoxic and stem-like potential, and inhibited exhaustion of NK and T cells; (3) mechanistically, DMC inhibited the expression of programmed cell death protein-1 and upregulated interferon-γ expression of NK and T cells via the gastrointestinal microbiota (Bacteroides acidifaciens, Odoribacter laneus, and Odoribacter splanchnicus)-AMPK-mTOR axis. Our study uncovers the role of DMC in improving the tumor microenvironment of HCC, which not only enriches the relationship between the mPGES-1/prostaglandin E2 pathway and the antitumor function of NK and T cells, but also provide an important strategic reference for multitarget or combined immunotherapy of HCC.Cite Now.
Improved extracellular vesicle-based mRNA delivery for familial hypercholesterolemia treatment
Authors: Zheng Yang, Panpan Ji, Zhelong Li, Rongxin Zhang, Mengying Wei, Yang Yang, Lijun Yuan, Yan Han, Guodong Yang
Journal: Theranostics (2023)

Extracellular vesicle (EV)-based low-density lipoprotein receptor (
RAB27B controls palmitoylation-dependent NRAS trafficking and signaling in myeloid leukemia
Authors: Jian-Gang Ren, Bowen Xing, Kaosheng Lv, Rachel A. O’Keefe, Mengfang Wu, Ruoxing Wang, Kaylyn M. Bauer, Arevik Ghazaryan, George M. Burslem, Jing Zhang, Ryan M. O’Connell, Vinodh Pillai, Elizabeth O. Hexner, Mark R. Philips, Wei Tong
Journal: Journal of Clinical Investigation (2023)

RAS mutations are among the most prevalent oncogenic drivers in cancers. RAS proteins propagate signals only when associated with cellular membranes as a consequence of lipid modifications that impact their trafficking. Here, we discovered that RAB27B, a RAB family small GTPase, controlled NRAS palmitoylation and trafficking to the plasma membrane, a localization required for activation. Our proteomic studies revealed RAB27B upregulation in CBL- or JAK2-mutated myeloid malignancies, and its expression correlated with poor prognosis in acute myeloid leukemias (AMLs). RAB27B depletion inhibited the growth of CBL-deficient or NRAS-mutant cell lines. Strikingly, Rab27b deficiency in mice abrogated mutant but not WT NRAS–mediated progenitor cell growth, ERK signaling, and NRAS palmitoylation. Further, Rab27b deficiency significantly reduced myelomonocytic leukemia development in vivo. Mechanistically, RAB27B interacted with ZDHHC9, a palmitoyl acyltransferase that modifies NRAS. By regulating palmitoylation, RAB27B controlled c-RAF/MEK/ERK signaling and affected leukemia development. Importantly, RAB27B depletion in primary human AMLs inhibited oncogenic NRAS signaling and leukemic growth. We further revealed a significant correlation between RAB27B expression and sensitivity to MEK inhibitors in AMLs. Thus, our studies presented a link between RAB proteins and fundamental aspects of RAS posttranslational modification and trafficking, highlighting future therapeutic strategies for RAS-driven cancers.
Abstract 12006: Lipoprotein(a), Coronary Atherosclerotic Plaque, and High-Risk Plaque in Asymptomatic Individuals: The Miami Heart Study at Baptist Health South Florida
Authors: Reed Mszar, Miguel Cainzos Achirica, Javier Valero Elizondo, Renato Quispe, Shozab S Ali, Lara Arias, Anshul Saxena, Ricardo C Cury, Matthew Budoff, Theodore Feldman, Shubham Lahan, Michael J Blaha, Michael D Shapiro, Garima Sharma, Raul D Santos, Jonathan Fialkow, Khurram Nasir
Journal: Circulation (2022)

Introduction: Affecting approximately 1 in 5 adults, elevated lipoprotein(a) [Lp(a)] levels are independently associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) events, however, the mechanisms driving this association are not fully understood. Therefore, we examined the association between Lp(a) and coronary plaque characteristics in a diverse U.S. cohort free of clinical ASCVD. Methods: We examined cross-sectional data from the Miami Heart Study, a prospective cohort study in South Florida conducted among asymptomatic adults 40-65 years of age who underwent CCTA. Those taking any lipid-lowering therapies were excluded. High Lp(a) was defined as ≥125 nmol/L. Outcomes included the following: any plaque on CCTA, coronary artery calcium score &gt;0, maximal stenosis ≥50%, presence of any high-risk plaque feature (positive remodeling, spotty calcification, low-attenuation plaque, napkin ring), and the presence of ≥2 high-risk plaque features. Logistic regression models were adjusted for demographics and other cardiovascular risk factors. Results: Among 1,795 participants, 291 (16.2%) had Lp(a) ≥125 nmol/L. In unadjusted analyses, Lp(a) ≥125 nmol/L was associated with a higher prevalence of all outcomes compared with Lp(a) &lt;125 nmol/L, however, differences were only statistically significant for any coronary plaque and the presence of ≥2 high-risk features ( Figure, Panel A ). In multivariable regression models, high Lp(a) was independently associated with the presence of any coronary plaque and ≥2 high-risk features ( Panel B ). Associations for the other outcomes trended in the same direction, however, the confidence intervals included the null. Conclusion: In this contemporary analysis of nearly 1,800 middle-aged asymptomatic adults undergoing CCTA, high Lp(a) was independently associated with any coronary plaque and the presence of multiple high-risk plaques.
Abstract 12178: Extracellular Vesicle-Encapsulated AAVs for Therapeutic Gene Delivery to the Heart
Authors: Sabrina La Salvia, Xisheng Li, Yaxuan Liang, Marta Adamiak, Erik Kohlbrenner, Estrella Lopez-Gordo, Anh Phan, Nikhil Raisinghani, shihong zhang, Edgar Gonzalez Kozlova, Nicole Dubois, Navneet Dogra, Roger Hajjar, Susmita Sahoo
Journal: Circulation (2022)

Background: Adeno-associated virus (AAV) has emerged as one of the best tools for cardiac gene delivery due to its cardiotropism, long-term expression, and safety. However, a significant challenge to its successful clinical use are pre-existing neutralizing antibodies (NAbs), which bind to free AAVs, prevent efficient gene transduction and reduce or negate therapeutic effects. Here we describe extracellular vesicle-encapsulated AAVs (EV-AAVs), secreted naturally by AAV-producing cells, as a superior cardiac gene delivery vector that delivers more genes and offers higher NAb resistance. Method: We developed a two-step density-gradient ultracentrifugation method to isolate highly purified EV-AAVs. Results: Using cardiotropic AAV serotypes 6 and 9 and several reporter constructs, we demonstrated that EV-AAVs deliver significantly higher quantities of genes than AAVs in the presence of NAb, both to human left ventricular and hiPSC cardiomyocytes in vitro, and to mouse hearts in vivo. Intramyocardial delivery of EV-AAV9-SERCA2a to infarcted hearts in pre-immunized mice significantly improved ejection fraction and fractional shortening compared to AAV9-SERCA2a delivery. These data validated NAb evasion by and therapeutic efficacy of EV-AAV9 vectors. Interestingly, in vivo trafficking studies in mouse hearts showed significantly higher expression of EV-AAV9-delivered genes in cardiomyocytes compared to non-cardiomyocytes, even with comparable cellular uptake. Using cellular sub-fraction analyses and pH-sensitive dyes, we discovered that EV-AAVs were internalized into acidic endosomal compartments of cardiomyocytes for releasing and acidifying AAVs for their nuclear uptake. Conclusion: Together, using six different in vitro and in vivo model systems, we demonstrate significantly higher potency and therapeutic efficacy of EV-AAV vectors compared to free AAVs. These results establish the potential of EV-AAV vectors as a gene delivery tool to treat heart failure. 1
Abstract 12453: Tricuspid Regurgitation After ICD Implantation is Rather Due to the Transvenous Lead Than Natural Progression
Authors: Karel T Breeman, Annelot J Peijster, rianne A de Bruin-bon, Shari Pepplinkhuizen, Willeke Van Der Stuijt, Jolien A De Veld, Niek E Beurskens, Martijn M Stuiver, Arthur A Wilde, Fleur V Tjong, Reinoud E Knops
Journal: Circulation (2022)

Introduction: Transvenous implantable cardioverter-defibrillators (TV-ICDs) are associated with greater tricuspid regurgitation (TR) severity, which leads to increased mortality. The pathophysiology is often assumed to be lead-related, hence, treatment includes lead extraction and alternative defibrillation strategies. However, TR may also be naturally occurring in the ICD population with a high risk of secondary TR, or may be caused by right ventricular pacing. Purpose: We aimed to evaluate the effect of ICD type (with or without lead) and pacing percentage on post-implantation TR severity. Methods: In this retrospective cohort study, we included consecutive patients with a first S-ICD or TV-ICD implantation between December 2009 until December 2019 and who underwent an echocardiography study ≤3 months before and ≤3 years post-implantation. TR severity at follow-up was adjusted for potential confounders using ordinal regression analysis. Results: 118 patients were included (mean age 52±21; 29% female), of whom 31 (26%) with an S-ICD and 87 (74%) with a TV-ICD. Follow-up echocardiography was performed median 20 months (IQR 14-29 months) after implantation. Worsening TR between pre- and post-implantation echocardiography was found in 11/31 (34%) patients with an S-ICD and 45/87 (52%) patients with a TV-ICD (p=0.15). Adjusted for age, atrial fibrillation, baseline TR and mitral regurgitation, ventricular pacing percentage and time since ICD implantation, TV-ICDs were significantly associated with greater TR severity at follow-up (OR 8.38, p=0.002). Ventricular pacing percentage was very low (5/118 [4%] were paced &gt;10%), and not significantly associated with greater TR severity (OR 0.97, p=0.123). Conclusions: Our results suggest that greater TR severity in ICD patients is mainly caused by the transvenous lead, rather than natural progression in the ICD population.
Abstract 12062: Additional Burden of Esophageal and Gastric Varices on Hospitalized Patients With Moderate or Severe Congenital Heart Disease
Authors: Hunter Culbert, Ciara June, Omar Meziab, Natalie E Caryl, Scott E Klewer, Michael D Seckeler
Journal: Circulation (2022)

Introduction: Elevated central venous pressure (CVP) occurs in many forms of congenital heart disease (CHD) which may result in esophageal or gastric varices. We sought to describe the incidence of varices and acute outcomes for hospital admissions with moderate or severe CHD compared to those without CHD. Methods: Vizient Clinical Database was queried from 10/2018-12/2021 for admissions aged 1-89 years with ICD-10 codes for moderate or severe CHD with and without ICD-10 codes for esophageal (I85-I85.11) or gastric (I86.4) varices. For comparison (NO-CHD), admissions with no CHD codes with and without varices were queried. Data included demographics, hospital outcomes, principal procedure and costs. Results: There were 54,979 CHD admissions, 489 (0.9%) with varices and 28,282,750 NO-CHD admissions, 231,633 (0.8%) with varices ( p = 0.069); summary in Table 1. Compared to the NO-CHD population, admission with CHD and varices were younger, had longer lengths of stay, higher complication rates and hospital costs with no difference in in-hospital mortality. Table 2 shows the top 5 principal procedures for each group. Conclusions: Hospitalized patients with moderate or severe CHD and varices have worse acute hospital outcomes and higher costs compared to those without CHD. These findings suggest a potential additional disease burden in this already fragile population. Future work to identify and potentially treat modifiable factors could improve care for these patients.
Abstract 12254: In-Hospital Or Out-of-Hospital Cardiac Arrest is Associated With Worse Outcomes in Cardiogenic Shock
Authors: Michael Yaoyao Yin, Jaime Hernandez-Montfort, Manreet Kanwar, Rachna Kataria, Vanessa Blumer, BORUI LI, Jacob Abraham, Arthur Reshad Garan, Shashank Sinha, Yijing Zhang, Shelley Hall, Paulina Baca, Fatou Dieng, Neil Harwani, Gavin W Hickey, Detlef Wencker, Wissam Khalife, Song Li, Ju H Kim, Esther Vorovich, Daniel Burkhoff, Navin K Kapur
Journal: Circulation (2022)

Background: Patient outcomes after cardiac arrest (CA) complicated by cardiogenic shock (CS) not related to acute myocardial infarction (non-AMI) remain poorly understood. The aim of our study was to assess differences in outcomes between non-AMI CS related to in-hospital cardiac arrest (IHCA) and out-of-hospital cardiac arrest (OHCA) using a real-world, multi-institutional registry. Methods: The CS Working Group (CSWG) registry is a retrospective dataset of patients hospitalized with CS from 17 clinical sites. A standardized set of data elements were collected between 2016 and 2021. Patients were identified as having either AMI or non-AMI related CS, and non-AMI related CS was further classified by acuity of etiology as acute-on-chronic heart failure (ACHF) and de novo HF. IHCA or OHCA were defined based on location of CA. The outcomes of this analysis were in-hospital mortality, renal replace therapy (RRT) and mechanical ventilation (MV). Results: There were 1767 patients (age 60.3 ± 14.6 years, 72.4% male) with non-AMI CS enrolled, of whom 1371 (77.6%) had ACHF and 349 (19.7%) had de novo HF. There were 152 (8.6%) IHCA and 103 (5.8%) OHCA. Mortality was higher for ACHF and de novo HF patients with IHCA compared with patients without IHCA, and was higher for ACHF patients with OHCA compared with patients without OHCA (Figure 1A-B). Rates of RRT were higher for ACHF and de novo HF patients with IHCA compared with patients without IHCA and was similar between ACHF and de novo HF patients with and without OHCA (Figure 1C-D). Rates of MV were higher for ACHF and de novo HF patients with IHCA or OHCA compared with ACHF and de novo HF patients without IHCA or OHCA (Figures 1E-F) . Conclusion: Outcomes are worse among patients with CA, irrespective of HF etiology or whether CA occurs in or out of the hospital. Further investigation is needed to better understand mechanisms contributing to these poor outcomes and to identify therapeutic targets for improvement.